Introduction: D-amphetamine induces symptoms of psychosis like those of schizophrenia in healthy individuals and aggravates them in schizophrenic patients1. Locomotor activity (LMA) in rodents can be manipulated during investigation of pharmacological agents concerning mania2. The aim of the present study was to investigate the pharmacodynamics of clinically-used antipsychotics in a drug-induced animal test, evaluating the clinical back-translation of these antipsychotics. The D2-selective antagonist sulpiride was utilized as a negative control due to its poor blood-brain-barrier permeability thus lack of effect at low doses3.

Methods: Adult male Wistar-Han rats were randomly grouped into dose groups/ saline alone ± d-amphetamine per antipsychotic (n=8) respectively. Rats were habituated in LMA arenas for 60-min prior to antipsychotic pretreatment of haloperidol (0.03, 0.1, 0.3), risperidone (0.1, 0.3, 1), clozapine (1, 3, 10, 30), aripiprazole (1, 3, 10, 30) and sulpiride (1, 3, 10, 30, 100) [s.c./i.p. mg/kg]. After 30-min, d-amphetamine was injected (s.c.) and data was recorded for 210-min. The total ambulatory move time was measured using TruScan-2 (Coulbourn-Instruments). Plasma was taken 60-min post-antipsychotic administration in satellite rats of similar weight, sex and age for HPLC analysis. The data is given as mean±SEM and analysed via one-way ANOVA with Dunnett’s test.

Conclusion: The results above indicate hyperlocomotion targeted pharmacodynamics and display the estimated Cu,brain in rat at MED of all apart from sulpiride is within 5-fold range of estimated Cu,brain of the known therapeutic plasma range in humans. Clozapine disconnection could be attributed to species differences in metabolism and active metabolites. As the pre-clinical correlates with clinical exposure, it suggests that this amphetamine-induced hyperlocomotion behavior test is suitable for pre-clinical MED for novel antipsychotics.